With the alarming rise of obesity and obesity related diseases, understanding the endocrine functions of adipose tissue is crucial because adipokines regulate systemic metabolism and insulin sensitivity. Inversely expressed with obesity, the adipokine adiponectin has positive metabolic effects via signaling in various tissues such as liver and skeletal muscle. Our laboratory has demonstrated differential efficacy of various sized adiponectin complexes, with sizes from 90 to 1080kDa, on insulin sensitivity. I hypothesize that the endothelium presents a transport barrier to adiponectin and may process the molecule for metabolic relevance. Our preliminary in vivo data demonstrate that adiponectin circulation time and half-life are size dependent. Our measured molecular sizes of adiponectin indicate transport limitations across the endothelium as being causative. Additionally, genetic analyses display changes in barrier function genes in endothelial cells and in vitro transwell studies demonstrate that adiponectin signaling on endothelial cells increases monolayer permeabilty to adiponectin and comparably-sized dextran molecules. These data strongly implicate the endothelium in actively modulating adiponectin transport and tissue accessibility. Therefore, in Aim 1, I intend to define the role of blood endothelial cells in adiponectin transport and determine by which molecular pathways adiponectin is made tissue accessible. In Aim 2, I propose that adiponectin enters circulation via lymphatic uptake and present experiments designed to demonstrate the necessity of this pathway, determine its modulators, and demonstrate its role in obesity. Preliminary data show adiponectin in interstitial fluid and within lymph nodes and the effect of dietary fat on peripheral lymphatic function. Aim 1 will utilize mouse models manipulating adiponectin or its receptors to examine adiponectin transport and in vitro systems of transport and molecular interactions with endothelial cells. For Aim 2, similar in vivo and in vitro systems will be used to explore interstitial transport and adipokine interaction with lymphatic endothelial cells. These two aims will allow me to fully define the mechanisms by which endothelial barriers modulate adiponectin transport and accessibility, and provide a potential basis for controling adipokine responses.